Download Alzheimer`s Disease

Alzheimer's
Disease
By:
Niazy B Hussam
PhD Clinical pharmcy
Alzheimer's disease



A disease of the nervous system characterized
by a progressive dementia that leads to
profound impairment in cognition and behavior
It is the most common form of dementia,
affecting 5% of individuals over age 65
The onset of the dementia typically occurs in
middle to late life, and the prevalence of the
illness increases with advancing age to include
25–35% of individuals over age 85.
Clinical Features









Earliest Feature
Memory loss
Late Features
Memory of remote events and overlearned informations
(for example, date and place of birth) declines together
with other cognitive abilities
Orientation to time is impaired
Declines in orientation to personal information and
immediate environment
Language deficits which gradually progress to a loss of all
language skills
Declines in abstract reasoning, judgment, and problem
solving
In the later stages of the disease, the individual is
bedridden and requires full-time assistance with basic
living skills
Neuropathological Features
 Senile
plaques
 Neurofibrillary tangles (NFT)
 Neuronal cell loss
 Other microscopic features include neuropil
threads, Hirano bodies, granulovascular
degeneration, and inflammation around
plaque formations
The areas commonly affected include the
association cortical and limbic regions
 Senile
plaques are extracellular and
contain a core of an amyloid beta peptide
(Aβ) that is derived from the cleavage of a
much larger beta amyloid precursor
protein (APP)
 Neurofibrillary tangle is a hyperphosphorylated tau protein producing a highly
insoluble cytoskeletal structure that is
associated with cell death
 Alzheimer's
disease has been associated with
dysfunction of several neurotransmitter systems
 Disruption of information transfer between neurons
can occur with loss of presynaptic elements and
reduction of the recognition sites at which the
neurotransmitter acts
 Loss of or abnormalities in the receptor-operated ion
channels and second messenger systems within cells
may be related to neuronal dysfunction
 Deficits in cholinergic, serotonergic, noradrenergic,
and peptidergic neurotransmitters have been
demonstrated
Diagnosis
A
definite diagnosis of Alzheimer's disease is
made only by direct examination of brain
tissue obtained at autopsy or by biopsy to
determine the presence of senile plaques
and neurofibrillary tangles.
 A clinical evaluation, however, can provide
a correct diagnosis in more than 80% of
cases
 Clinical




evaluation:
Clinical history
Neurological and psychiatric examinations
Laboratory tests are used to screen for medical
conditions, including diabetes, renal dysfunction,
hypothyroidism, infection, and vitamin deficiencies.
Neuroimaging studies
Risk Factors
 Advancing
age
 Family history
 APOE 4 genotype
 Obesity
 Insulin resistance
 Vascular factors
 Dyslipidemia
 Hypertension
 Inflammatory markers
 Down syndrome
 Traumatic brain injury
Pathophysiology of AD
 The
pathophysiology of AD is largely unknown
 The Amyloid Cascade Hypothesis is the main
proposed mechanism to explain the disease process
 Abnormal production or insufficient clearance of the
Aβ protein is thought to result in extracellular amyloid
plaque deposition, which in turn leads to secondary
events, such as hyperphosphorylation of the protein
tau and generation of NFTs, inflammation,
excitotoxicity, and, eventually, cell death through
activation of the apoptotic pathway
APP
α-Secretase
β-Secretase
sAPPα
sAPPβ
γ-Secretase
γ-Secretase
p3
NFTs
Aβ
Inflammation
Oxidative
Stress
Excitotoxicity
Figure 1 Amyloid cascade hypothesis in AD
 An
alternate hypothesis considers NFTs at the center
of the pathophysiological process
 NFTs are produced by hyperphosphorylation of the
protein tau, which is usually responsible of stabilizing
the axonal cytoskeleton. They lead to disruption in
axonal transport and eventually to cell death
 In recent years, increased emphasis has been put
on
the
vascular
contribution
to
AD’s
pathophysiology
Treatment
 Cholinesterase
Inhibitors: ChEIs improve
symptoms of AD, but they do not alter its
natural clinical course.
 Donepezil
 Rivastigmine
 Galantamine
 Glutamate receptor antagonist
 Memantin
Management of Side Effects.





ChEIs are associated with cholinergic side effects
S/E are observed with all available ChEIs
Dose-dependent
Starting these agents at the lowest dose, and
slowly titrating by no less than 4-week intervals to
the minimally effective dose, helps to minimize
these side effects
The transdermal formulation of rivastigmine is
associated with considerably less gastrointestinal
cholinergic side effects
Switching Agents



ChEIs belong to the same general class, yet,
their individual pharmacological properties
make switching a feasible option for
intolerance or for lack of clinical response
In the case of intolerance, wait for complete
resolution of side effects of the initial agent
before switching to the second agent
In the case of lack of clinical response,
switching to the second agent can be done
overnight, with quicker titration
Discontinuation of Therapy
Indications for discontinuation of therapy in AD
1. The patient and (or) their proxy decision maker decide to
stop
2. Refusal to take the medication
3. Non adherence to the medication
4. No response to therapy after a reasonable trial
5. Intolerable side effects
6. Comorbidities making continued use of the agent risky or
futile
7. Progression to a stage of the disease where there is no
significant benefit from continued therapy

Emerging Treatments
 Amyloid-Based Therapies


Reducing Aβ Production
Preventing Aβ Accumulation and Promoting Clearance
 Nonamyloid

Strategies
Tau-Targeted Therapies
 Other Downstream




Processes to Target :
Inflammation
Oxidative stress
Excitotoxicity
Mitochondrial dysfunction